The long term goal of these studies is to determine which chromosome 21 genes result in the characteristic congenital heart disease of Down syndrome when present in three copies. In addition, we wish to determine which chromosome 21 gene result in the presenile dementia and Alzheimer-like neuropathological changes found in Down syndrome. Based on rare patients who are trisomic for a small segment of chromosome 21 in the region of SOD1 and who have congenital heart disease, our working hypothesis is that three copies of a gene or genes in the SOD1 region of chromosome 21 causes heart disease. Based on the tight linkage of the human 21 DNA probe D21S16 to a locus causing autosomal dominant Alzheimer's disease, we hypothesize that trisomy for a gene or genes in the D21S16 region of the chromosome results in the presenile dementia of Down syndrome. To test these hypotheses, we propose to isolate the 10,000 kb regions of human chromosome 21 around SOD1 and D21S16, will be used to define a physical map of each chromosomal region at the 100 kb level of resolution. Analogous physical maps will be constructed for the homologous regions of the mouse genome, and by comparing the position of crosshybridizing probes, the degree of homology between the mouse and human segments will be determined at the molecular level. The isolation and physical maps of these chromosomal segments will provide reagents to test the feasibility of introducing large human chromosome 21 fragments into pluripotent mouse teratocarcinoma cells by protoplast fusion with yeast containing artificial human chromosomes. Ultimately, these cell lines will be used to create "transgenic" mice, which will serve as an in vivo assay system to determine those chromosome 21 regions responsible for heart disease and Alzheimer-like changes in Down syndrome.